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Int J Radiat Oncol Biol Phys. 2014 November 15; 90(4): 863869. doi:10.1016/j.ijrobp.2014.07.031.
Proton Radiotherapy for the Treatment of Retinoblastoma

Kent W Mouw, MD PhD1,2, Roshan V Sethi, BS2, Beow Y Yeap, ScD2, Shannon M
MacDonald, MD2, Yen-Lin E. Chen, MD2, Nancy J Tarbell, MD2, Torunn I Yock, MD MCH2,
John E Munzenrider, MD2, Judith Adams, CMD2, Eric Grabowski, MD ScD3, Shizuo Mukai,
MD4, and Helen A Shih, MD2
1Harvard
Radiation Oncology Program, Boston, MA
2Department
of Radiation Oncology, Massachusetts General Hospital, Boston, MA
3Department
of Pediatrics, Massachusetts General Hospital, Boston, MA
4Retina
Service, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Boston, MA
Abstract
PurposeTo investigate long-term disease and toxicity outcomes for pediatric retinoblastoma
patients treated with proton radiotherapy (PRT).
Methods and MaterialsThis is a retrospective analysis of 49 retinoblastoma patients (60
eyes) treated with PRT between 1986 and 2012.
ResultsThe majority (84%) of patients had bilateral disease, and nearly half (45%) had
received prior chemotherapy. At a median follow-up of 8 years (range, 1 24 years), no patients
died of retinoblastoma or developed metastatic disease. The post-PRT enucleation rate was low
(18%), especially in patients with early-stage disease (11% for patients with International
Classification for Intraocular Retinoblastoma [ICIR] Stage A-B disease vs 23% for patients with
ICIR Stage C-D disease). Post-PRT ophthalmologic follow-up was available for 61% of the
preserved eyes (30/49): 14/30 eyes (47%) had 20/40 visual acuity or better, 7/30 (23%) had
moderate visual acuity (20/40 - 20/600), and 9/30 (30%) had little or no useful vision (worse than
20/600). Twelve of 60 treated eyes (20%) experienced a post-PRT event requiring intervention,
with cataracts the most common (4 eyes). No patients developed an in-field second malignancy.
ConclusionsLong-term follow-up of retinoblastoma patients treated with PRT demonstrates
that PRT can achieve high local control rates, even in advanced cases, and many patients retain
2014 Elsevier Inc. All rights reserved.

Corresponding Author: Helen A Shih MD, Massachusetts General Hospital, Department of Radiation Oncology, 30 Fruit St., Boston,
MA 02114, Phone: 617-724-9627, Fax: 617-724-9532.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
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Portions of this work were presented at the 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO), Atlanta,
GA, Sept. 22-25th, 2013.
Conflicts of interest:
H Shih is a senior editor of the IJROBP.
Mouw et al.
Page 2
useful vision in the treated eye. Treatment-related ocular side effects were uncommon and no
radiation-associated malignancies were observed.
INTRODUCTION
Retinoblastoma is the most common intraocular malignancy of childhood, and nearly 300
new cases are diagnosed each year in the US. [1, 2] Approximately 60% of tumors are
sporadic, while 40% are hereditary owing to germline loss or mutation of the RB1 tumor
suppressor gene.[2, 3] Sporadic cases of retinoblastoma are typically unilateral, whereas
most patients with hereditary disease present with bilateral tumors. Although not
uncommonly seen in developing countries, metastases are rare at diagnosis in North
America; therefore, definitive management relies on effective treatment of the ocular
tumor(s).
External beam radiation therapy (EBRT) has been used in the treatment of retinoblastoma
for over a century and was the preferred vision-sparing treatment approach for many years.
[4-6] Long-term eye preservation rates range from 50-100% in several large series, with
outcomes better for early-stage versus advanced tumors.[7-9] However, use of EBRT has
decreased sharply over the past two decades owing to the advent of effective
chemotherapeutic regimens as well as concern for radiation-induced side effects including
growth abnormalities and second malignancies.[10-13] Currently, EBRT is typically
reserved for cases of progressive or persistent disease following chemotherapy and focal
treatment (cryotherapy or laser photocoagulation/thermotherapy), or in advanced cases when
vitreous or subretinal seeding is present.[14, 15] Even in these advanced or refractory cases,
ocular salvage and vision preservation can often be achieved.[5, 7]
EBRT techniques have evolved significantly over time and conformal photon techniques
and proton RT (PRT) are now favored for treatment of retinoblastoma.[16, 17] Due to its
unique physical properties and lack of exit dose, PRT minimizes normal tissue exposure and
may be associated with lower rates of radiation-induced normal tissue injury and
malignancies compared to contemporary photon-based techniques.[18] PRT has been used
in the treatment of retinoblastoma at our institution since 1986, and here we report the longterm outcomes of patients treated with this approach.
METHODS
Patient Population
We identified all patients who received PRT for retinoblastoma at our institution between
1986 and 2010 and who had at least one year of follow-up data available (4 patients
excluded due to inadequate follow-up). Patients with extraocular tumors or who had
received previous radiation (EBRT or brachytherapy) were excluded from the analysis (N =
5). Patients receiving PRT following enucleation were also excluded (N = 3). For eligible
patients, all available medical records were analyzed. This study was approved by our
institutional review board.
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Treatment Details
All patients underwent exam under anesthesia (EUA) at the time of initial evaluation. Tumor
stage was assigned based on description of EUA findings using the International
Classification for Intraocular Retinoblastoma (ICIR) staging system.[19] Computed
tomography (CT)-based radiation planning was performed for all patients, and patients were
treated at XXXX. The target volume was defined jointly by the treating radiation oncologist
and the ophthalmologist and contained the tumor(s) plus a margin of 5-8 mm depending
upon treating physician preference. For large retinal tumors or tumors with vitreous seeding,
the entire vitreous and retina were targeted with the anterior field edge placed just posterior
to the lens and typically correlating with the ora serrata. For smaller tumors of the posterior
retina, a single anterior oblique beam was used to minimize exposure of the bony orbit
(Figure 1). Patients were treated under general anesthesia using a custom head
immobilization device as well as a radio-opaque silicon suction cup to maintain a neutral
forward gaze position during treatment. A custom brass aperture and range compensator
were fashioned to control the shape and depth of the beam. A 3.5% CT density correction
plus 1 mm were applied for range uncertainty, and 1 mm lateral margin was added to
aperture edge for set up uncertainty.
Follow-Up
Patients underwent EUA at the completion of RT to establish a post-treatment baseline, and
then at lengthening intervals if they remained disease-free. Aside from the CT performed for
radiation planning, no radiographic studies were routinely performed during treatment or
follow-up. Length of follow-up was defined as the time from start of RT to the most recent
recorded status of the treated eye(s).
Statistical Analysis
Fishers exact test was used to compare clinical and demographic characteristics between
patient groups for binary outcomes. Wilcoxon-rank sum test was used for group comparison
when the data were continuous or ordinal, including the three-category visual outcomes.
Enucleation-free survival was defined from the first day of PRT until the date of enucleation
or was censored at the date of last follow-up for non-enucleated eyes. Enucleation-free
survival was estimated by the Kaplan-Meier method, with the differences between groups
assessed by the log-rank test. All p-values are based on a two-sided hypothesis. Data
analysis was performed using SAS 9.3 (SAS Institute, Cary, NC), while StatXact 6.0 (Cytel
Software, Cambridge, MA) was used to compute the exact p-values in the analysis of
enucleation-free survival and visual outcomes.
RESULTS
Patient and Treatment Characteristics
A total of 49 patients and 60 irradiated eyes were included in the analysis (Table 1).
Approximately half of the patients (26/49, 53%) were female. The median age at diagnosis
was six months and ranged from six days to 30 months.
Mouw et al.
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Twenty-nine of the 49 patients (59%) presented with clinical signs of retinoblastoma.

Leukocoria was the most common sign (18/29), followed by strabismus or head tilt (10/29).
Approximately one quarter of patients were diagnosed by screening (12/49), and these
patients were diagnosed at a significantly younger age than patients presenting with clinical
signs (2.3 months vs 9 months; p=0.0003). The events preceding diagnosis were unknown
for eight patients (16%).
Fourteen patients (29%) had a family history of retinoblastoma (defined as retinoblastoma in
a first-degree relative), and these patients were diagnosed at a significantly younger age (1.8
months vs 11 months; p<0.0001) and were significantly more likely to be diagnosed by
screening (92% vs 3%; p<0.0001) than patients without a family history. Ten of the 14
patients (71%) with a positive family history had bilateral tumors at diagnosis.
A total of 60 tumors were treated with PRT, and these were approximately equally split
between early-stage (27/60 [45%] ICIR Stage A or B) and advanced-stage (31/60 [52%]
ICIR Stage C-D) cases (Table 1). Of the 27 patients with early-stage disease, 15 (56%) had
Stage B disease due to documented involvement of the optic disc and/or fovea. Two tumors
(3%) lacked adequate information to determine the stage. No Stage E tumors were treated
with PRT.
Bilateral tumors were present in 41 of the 49 patients (84%). Eleven of 41 patients with
bilateral disease underwent bilateral PRT. Enucleation of one eye prior to irradiation of the
other eye was performed in 23 patients, and seven patients received focal therapy (laser
photocoagulation or cryotherapy) alone to the non-irradiated eye.
Approximately half of patients (25/49, 51%) received chemotherapy in addition to PRT.
Nearly all of these patients received upfront chemotherapy (22/25), and subsequently
required PRT for progressive or recurrent disease. One patient received chemotherapy after
PRT and two received chemotherapy both before and after PRT. A variety of chemotherapy
regimens were used, with carboplatin, vincristine, and etoposide being the most common
agents. Patients with Stage C-D tumors were significantly more likely to be treated with
chemotherapy prior to PRT than patients with Stage A-B tumors (68% vs 30%; p=0.008).
A majority of the irradiated eyes (43/60, 72%) were also treated using focal techniques
(laser photocoagulation and/or cryotherapy). Twenty-five of the 43 eyes underwent focal
treatment prior to PRT (typically at the time of diagnosis or during chemotherapy), 12 were
treated after PRT (due to concern for non-regressing tumor), and six were treated both
before and after PRT.
The median prescribed radiation dose was 44 Gy(RBE), and the range was 40 to 46.8
Gy(RBE). Radiation was given in 1.8 to 2.0 Gy(RBE) daily fractions delivered four or five
times per week. The median age at the start of radiation was 14 months (range, 27 days 82
months), and the median time from diagnosis to the start of radiation was 83 days (range, 2
days 62 months). In patients not receiving chemotherapy prior to radiation, the median
time between diagnosis and the start of radiation was 21 days, compared to 7 months in
patients undergoing chemotherapy prior to radiation (p<0.0001).
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Tumor Control & Enucleation Free Survival
The median length of follow-up in this cohort was 8 years (range, 1 24 years) and the
median patient age at the time of last follow-up was 9 years (range, 2 24 years) (Table 2).
No patients died of retinoblastoma and none developed metastatic disease during follow-up.
No patients developed an in-field second malignancy; however, one patient with hereditary
disease developed an osteosarcoma of the femur 10 years after completion of radiation for
retinoblastoma.[18]
Eleven of 60 irradiated tumors (18%) ultimately required enucleation. Three of 27 Stage AB tumors (11%) required enucleation following PRT, as did seven of 31 Stage C-D tumors
(23%) (Table 2 and Figure 2A-B). All but one of enucleations took place within two years of
completion of PRT, and no enucleations took place beyond four years. Five enucleations
occurred among the 24 patients who did not receive chemotherapy, five occurred among 24
patients who received chemotherapy before (or before and after) PRT, and one enucleation
occurred in the single patient who received chemotherapy after (but not before) PRT. There
was no difference in enucleation-free survival among patients who received chemotherapy
or focal therapy and those who did not (Figure 2C-D).
The most common indication for enucleation was tumor progression (8/11), followed by
non-tumor ocular complication (2/11). The indication and date for one enucleation was
unknown. There was no difference in the median time interval from completion of PRT to
enucleation for enucleations performed for progressive disease versus enucleations
performed for non-tumor ocular complications (14 months vs 8 months, p=0.533). Radiation
dose and overall treatment time were similar between enucleated and non-enucleated eyes.
Approximately half (6/11) of the enucleations were performed at our institution, and half
(5/11) were performed at an outside institution. The median time from completion of PRT to
enucleation was 10 months (range, 5 44 months), and there was a trend towards a longer
median time interval between completion of PRT and enucleation when the enucleation was
performed at our institution versus another institution (20 months vs 7 months; p=0.067).
Ocular Complications
Twelve of 60 irradiated eyes (20%) in 11 of the 49 patients (22%) developed a posttreatment ocular complication requiring procedural correction. All but one of the eyes
requiring an intervention had a Stage C-D tumor at diagnosis. Two of the twelve eyes
eventually required enucleation for persistent ocular complication. Cataracts were the most
common complication (4/12), followed by radiation retinopathy (3/12), glaucoma (1/12),
neovascularization (1/12), other complications (2/12), and one eye with multiple
complications (1/12). The complications eventually requiring enucleation were multiple (1
case) and neovascularization with hemorrhage (1 case).
Visual Outcomes
Formal ophthalmologic follow-up information was available for 61% (30/49) of nonenucleated irradiated eyes. Visual outcomes were characterized as good (20/40 visual acuity
or better in treated eye), moderate (worse than 20/40 but better than 20/600), or poor (worse
Mouw et al.
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than 20/600) based on the most recent available ophthalmologic evaluation (Figure 3).
Fourteen of 30 evaluated eyes (47%) had 20/40 visual acuity or better following PRT,
including 7 of 15 eyes (47%) with Stage A-B disease and 7 of 14 eyes (50%) with Stage CD disease. Seven of 30 treated eyes (23%) had moderate visual acuity (3 of 15 Stage A-B
eyes [20%]; 3 of 14 Stage C-D eyes [21%]; one eye with unknown stage), and 9 of 30
treated eyes (30%) had poor visual acuity (5 of 15 Stage A-B eyes [33%] and 4 of 14 Stage
C-D eyes [29%]). The subset of eyes with Stage B disease due to involvement of the optic
disc or fovea had worse outcomes than other Stage A-B tumors (p=0.005) (Figure 3). Of
seven eyes with optic disc or fovea involvement at diagnosis, there were three moderate and
four poor visual acuity outcomes, suggesting that tumor location at diagnosis impacts visual
outcomes following PRT. There did not appear to be differences in visual outcomes between
patients who received chemotherapy and those who did not (p=0.289), or between eyes that
received pre-PRT focal therapy and those that did not (p=0.287).
Cosmetic outcomes were often reported by providers at follow-up, and one third of patients
(16 of 49, 33%) (including 3 patients with 2 outcomes each) had documented physical exam
findings likely attributable to PRT, including orbital hypoplasia (15/49), hyperpigmentation
(3/49), or soft tissue fibrosis over the treatment portal (1/49). Due to lack of standardized
reporting, actual rates of cosmetic side effects of PRT may be higher; however, no
procedures to address PRT-related cosmetic issues were recorded in this cohort.
DISCUSSION
Here, we report long-term outcomes of retinoblastoma patients treated with PRT. To our
knowledge, this represents the largest and most mature experience available for this patient
population.
For nearly a century, photon-based radiotherapy was the standard of care for retinoblastoma
patients and was associated with high rates of disease control and vision preservation.[4, 5,
7-9, 20] However, patients remained at significant risk for toxicities including growth
abnormalities and radiation-induced malignancies resulting from collateral irradiation of
adjacent normal tissues.[7, 18, 21] In the past two decades, chemotherapy and focal
treatments such as laser photocoagulation, cryotherapy, and episcleral brachytherapy have
largely replaced EBRT in upfront treatment.[15] The cohort studied here represents patients
from both eras: approximately one half of patients received PRT as primary treatment,
whereas half (typically with more advanced disease) often received chemotherapy and/or
focal treatments prior to PRT.
Among patients with advanced tumors who received PRT, disease control and eye
preservation rates were quite high. Importantly, no patients in this cohort died of
retinoblastoma or developed metastatic disease. Despite many of these patients receiving
multiple treatments prior to PRT, approximately 75% of Stage C-D patients were able to
preserve the treated eye. In approximately half of the preserved eyes, good visual outcomes
(20/40 visual acuity or better) were achieved following PRT, and another 21% of patients
had moderate visual acuity (20/40 to 20/600) following treatment. Patients with more
advanced tumors did have higher rates of ocular complications than early-stage patients,
Mouw et al.
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with all but one of the noted complications occurring in Stage C-D patients. However, given
that the majority of these patients had exhausted other treatment options, PRT appears to
represent a safe alternative to enucleation and allows the majority of appropriately selected
patients to be cured of their disease and preserve useful vision.
Approximately half of the tumors in this cohort (27/60, 45%) were early-stage (ICIR Stage
A-B), and almost half of these patients (11/27, 41%) received PRT in the upfront setting.
Eye preservation rates were very high and complication rates very low in this setting. Only
11% of Stage A-B tumors were not controlled with PRT and eventually required enucleation
of the affected eye. Similarly, complications were uncommon, with only one preserved eye
requiring a procedure following PRT. Given the favorable outcomes and minimal observed
toxicity, PRT may be an appropriate upfront treatment for carefully selected early-stage
tumors. However, because patients incur a lifetime elevated risk of radiation-induced
malignancies, long term follow-up is necessary.
Interesting, there appeared to be two distinct subgroups with the early-stage patients with
respect to visual acuity outcomes. Most patients with Stage A-B tumors that did not involve
the optic disc or fovea had good visual acuity outcomes, whereas patients who had Stage B
tumors with EUA-documented optic disc or fovea involvement had significantly worse
outcomes (Figure 3). Due to the young age at presentation, none of the patients in this cohort
had pre-treatment visual acuity testing. Therefore, it is not possible to determine the relative
contribution of the tumor versus the treatment towards long-term visual outcomes. However,
the relatively poor outcomes among patients with Stage B disease with optic disc/fovea
involvement, even relative to patients with Stage C-D disease (which includes large tumors
and presence of vitreous seeding), suggest that tumor location may play a significant role in
determining post-treatment visual acuity. Achieving good visual acuity outcomes has proven
to be difficult for tumors involving the optic disc or fovea whenever local therapy
(cryotherapy, laser photocoagulation, or photon- or proton-based RT) is necessary;
therefore, continued focus on developing new therapies remains an important goal for the
field.
Given the relative rarity of retinoblastoma, newly-diagnosed patients are often referred to
specialized centers for work-up and treatment. With the high success rates of modern
therapies, the majority of patients can be cured of their disease. However, patients are often
not able to return for routine follow-up at the treating center, and are instead followed
locally. Practitioners unfamiliar with either the disease or expectant post-PRT treatment
response of tumor stabilization with slow regression may find it difficult to distinguish PRT
treatment effect versus tumor progression. Careful monitoring with serial EUAs is often
required to discern between active and regressing tumor. We note a trend towards shortened
time from end of PRT to enucleation for enucleations performed at outside institutions
compared to enucleations performed at our institution and speculate that some of the
enucleated cases at outside institutions may represent slowly responding tumors rather than
true failures. Pathology was not available for these cases; however, even if available,
responding tumor may not appear histologically different from viable disease despite its
incapacity to proliferate.
Mouw et al.
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Due to the unique physical properties of the proton beam, PRT represents the most
conformal external beam radiation treatment option currently available for retinoblastoma.
For the majority of early-stage cases in this cohort, the target was limited to the tumor(s)
plus a small margin of 5-8 mm, thus sparing dose to uninvolved portions of the anterior
retina, cornea, and lens. For more advanced tumors with seeding, the entire vitreous was
treated in order to ensure full coverage of the involved areas. A single field was adequate to
cover either of these treatment volumes, thus limiting normal tissue exposure to a small
region of low-intermediate dose between the skin surface and the globe (Figure 1). Unlike
photon-based RT, radiation to other facial structures and the CNS can be eliminated or
markedly reduced with PRT. However, due to the entrance dose of the proton beam through
the lateral or anterior oblique treatment portal, orbital hypoplasia and skin changes can
occur, and were noted in a significant percentage of this cohort. Prospective studies are
warranted to systematically characterize the long-terms effect of PRT on toxicity and
quality-of-life.
In summary, long-term disease control can often be achieved with PRT in both early-stage
and advanced tumors. Useful vision was preserved in the majority of cases; however, visual
outcomes appear to depend upon the extent of tumor involvement of the optic disc and fovea
at diagnosis. Ocular toxicities were more common among advanced tumors, but overall rates
were low. Importantly, no radiation-associated malignancies were noted in this cohort.
REFERENCES
1. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999-2009 Incidence and
Mortality Web-based Report. 2013. Available from: http://www.cdc.gov/uscs
2. Ries, L.; Smith, M.; Gurney, J., et al., editors. Cancer Incidence and Survival among Children and
Adolescents: United States SEER Program 1975-1995. National Institute of Health; Bethesda (MD):
1999.
3. Sachdeva UM, OBrien JM. Understanding pRb: toward the necessary development of targeted
treatments for retinoblastoma. J Clin Invest. 2012; 122:42534. [PubMed: 22293180]
4. Cassady JR, Sagerman RH, Tretter P, et al. Radiation therapy in retinoblastoma. An analysis of 230
cases. Radiology. 1969; 93:4059. [PubMed: 5822720]
5. Blach LE, McCormick B, Abramson DH. External beam radiation therapy and retinoblastoma: longterm results in the comparison of two techniques. Int J Radiat Oncol Biol Phys. 1996; 35:4551.
[PubMed: 8641925]
6. Hilgartner H. Report of a case of double glioma treated by x-rays. Tex Med J. 1903; 18
7. Abramson DH, Beaverson KL, Chang ST, et al. Outcome following initial external beam
radiotherapy in patients with Reese-Ellsworth group Vb retinoblastoma. Arch Ophthalmol. 2004;
122:131623. [PubMed: 15364710]
8. Merchant TE, Gould CJ, Hilton NE, et al. Ocular preservation after 36 Gy external beam radiation
therapy for retinoblastoma. J Pediatr Hematol Oncol. 2002; 24:2469. [PubMed: 11972090]
9. Schipper J, Tan KE, van Peperzeel HA. Treatment of retinoblastoma by precision megavoltage
radiation therapy. Radiother Oncol. 1985; 3:11732. [PubMed: 3920733]
10. Jairam V, Roberts KB, Yu JB. Historical trends in the use of radiation therapy for pediatric
cancers: 1973-2008. Int J Radiat Oncol Biol Phys. 2013; 85:e1515. [PubMed: 23273995]
11. Marees T, van Leeuwen FE, de Boer MR, et al. Cancer mortality in long-term survivors of
retinoblastoma. Eur J Cancer. 2009; 45:324553. [PubMed: 19493675]
12. Yu CL, Tucker MA, Abramson DH, et al. Cause-specific mortality in long-term survivors of
retinoblastoma. J Natl Cancer Inst. 2009; 101:58191. [PubMed: 19351917]
Mouw et al.
Page 9

13. Wong FL, Boice JD Jr. Abramson DH, et al. Cancer incidence after retinoblastoma. Radiation dose
and sarcoma risk. JAMA. 1997; 278:12627. [PubMed: 9333268]
14. Shields CL, Honavar SG, Meadows AT, et al. Chemoreduction plus focal therapy for
retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or
enucleation. Am J Ophthalmol. 2002; 133:65764. [PubMed: 11992863]
15. Rodriguez-Galindo C, Chantada GL, Haik BG, et al. Treatment of retinoblastoma: current status
and future perspectives. Curr Treat Options Neurol. 2007; 9:294307. [PubMed: 17580009]
16. Krengli M, Hug EB, Adams JA, et al. Proton radiation therapy for retinoblastoma: comparison of
various intraocular tumor locations and beam arrangements. Int J Radiat Oncol Biol Phys. 2005;
61:58393. [PubMed: 15667981]
17. Lee CT, Bilton SD, Famiglietti RM, et al. Treatment planning with protons for pediatric
retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other
conformal techniques? Int J Radiat Oncol Biol Phys. 2005; 63:36272. [PubMed: 16168831]
18. Sethi RV, Shih HA, Yeap BY, et al. Second nonocular tumors among survivors of retinoblastoma
treated with contemporary photon and proton radiotherapy. Cancer. 2014; 120:12633. [PubMed:
24122173]
19. Linn Murphree A. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol
Clin North Am. 2005; 18:4153. [PubMed: 15763190]
20. Pradhan DG, Sandridge AL, Mullaney P, et al. Radiation therapy for retinoblastoma: a
retrospective review of 120 patients. Int J Radiat Oncol Biol Phys. 1997; 39:313. [PubMed:
9300734]
21. Kleinerman RA, Yu CL, Little MP, et al. Variation of second cancer risk by family history of
retinoblastoma among long-term survivors. J Clin Oncol. 2012; 30:9507. [PubMed: 22355046]

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SUMMARY
Radiotherapy (RT) can be used in the primary or salvage treatment of retinoblastoma and
has been associated with high cure rates but also with risk of radiation-related
complications. Here, we present long-term follow-up for a large cohort of retinoblastoma
patients treated with proton RT. Despite many patients having advanced disease, tumor
control rates are high and functional vision is preserved in the majority of patients.
Ocular toxicity was limited, and no radiation-associated malignancies were observed.

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Figure 1.
Representative axial CT slice from two PRT plans. A. For small tumors without seeding, a
single anterior oblique beam was used to minimize dose to the bony orbit (prescription dose
44 Gy[RBE]). The tumor is outlined in red, and the lens is outlined in pale green. B. For
larger tumors, or if seeding was present, the posterior chamber was targeted with a single
lateral beam (prescription dose 45 Gy[RBE]).

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Figure 2.
Enucleation-free survival (EFS). A. EFS for all PRT-treated eyes. B. EFS stratified by ICIR
tumor stage. C. EFS stratified by use of pre-PRT chemotherapy. D. EFS stratified by use of
focal therapy.

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Figure 3.
Visual Outcomes. PRT-treated eyes with formal ophthalmologic evaluation were grouped by
visual acuity into good (20/40 or better), moderate (20/40 to 20/600), or poor (worse than
20/600) outcome categories. The percentage of eyes in each category are shown for Stage AB tumors without optic disc or fovea involvement, Stage B tumors with optic disc and/or
fovea involvement, and Stage C-D tumors.

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Table 1
Patient and Treatment Characteristics
No. patients
49
Female
26 (53%)
Male
23 (47%)
Mechanism of Diagnosis (N=49)

Screening
12 (25%)
Clinical Sign(s)
29 (59%)
Leukocoria/abnormal light reflex
18/29
Strabismus or head tilt
10/29
Eye swelling
1/29
Unknown
8 (16%)
No. patients with positive family history for retinoblastoma
14/49 (29%)
Positive family history and bilateral disease
10/14
Positive family history and diagnosis by screening
11/14
Median Age at Diagnosis (range)
6 mo (6 d - 30 mo)
Patients identified by screening (range)
70 days (6 d - 8 mo)
Patients identified by clinical sign(s) (range)
9 months (1 - 30 mo)
Patients with positive family history (range)
55 days (6 d - 8 mo)
Patients without positive family history (range)
11 mo (45 d - 30 mo)
No. patients with bilateral disease at diagnosis
41/49 (84%)
Received bilateral PRT
11/41
Contralateral enucleation prior to PRT
23/41
Local therapy only to contralateral eye
7/41
ICIR Stage at Diagnosis (N=60)
Stage A-B without disc/fovea involvement
12 (20%)
Stage B due to disc/fovea involvement
15 (25%)
Stage C-D
31 (52%)
Stage unrecorded
No. patients who received chemotherapy
2 (3%)
25/49 (51%)
Prior to PRT
22/25
After PRT
1/25
Before and after PRT
2/25
No. eyes treated with cryotherapy/laser

Before PRT
43/60 (72%)
25/43
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After PRT
12/43
Before and after PRT
6/43
Median age at PRT start (range)

Median time elapsed between diagnosis and RT start (range)
Median time elapsed for patients not receiving chemo
Median time elapsed for patients receiving chemo
Median PRT dose, Gy(RBE) (range)
14 mo (1 - 82 mo)
83 days (2 d - 62 mo)
21 days
7 mo
44.0 (40-46.8)
ICIR: International Classification for Intraocular Retinoblastoma

Mouw et al.
Page 16
Table 2
Follow-Up Details
Median length of follow-up (range)
8 yrs (1 -24 yrs)
Median age at last follow-up (range)
9 yrs (2 - 24 yrs)
No. irradiated eyes enucleated
11/60 (18%)
Stage A-B
3/11
Stage C-D
7/11
Stage unknown
1/11
Enucleation location
Our institution
6 (55%)
Outside institution
5 (45%)
Median time elapsed between PRT and enucleation (range)
10 mo (5 - 44 mo)
Median time when enucleation at our institution
20 mo
Median time elapsed when enucleation at outside institution
7 mo
Indication for Enucleation

Progressive disease
8/11
Ocular complications
2/11
Unknown
1/11
Non-enucleative ocular complications requiring procedure

Cataracts
Radiation retinopathy
Glaucoma
Neovascularization/Hemorrhage
Other
Multiple
No. patients with metastatic disease
No. patients with second malignancy
No. patients with in-field second malignancy

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Published in final edited form as:

Proton Radiotherapy for the Treatment of Retinoblastoma

Radiation Oncology Program, Boston, MA

of Radiation Oncology, Massachusetts General Hospital, Boston, MA

of Pediatrics, Massachusetts General Hospital, Boston, MA

Service, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Boston, MA

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2014 Elsevier Inc. All rights reserved.

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Twenty-nine of the 49 patients (59%) presented with clinical signs of retinoblastoma.

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Tumor Control & Enucleation Free Survival

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Patient and Treatment Characteristics

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Mechanism of Diagnosis (N=49)

Leukocoria/abnormal light reflex

Strabismus or head tilt

No. patients with positive family history for retinoblastoma

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Positive family history and bilateral disease

Positive family history and diagnosis by screening

Median Age at Diagnosis (range)

Patients identified by screening (range)

Patients identified by clinical sign(s) (range)

Patients with positive family history (range)

Patients without positive family history (range)

No. patients with bilateral disease at diagnosis

Received bilateral PRT

Contralateral enucleation prior to PRT

Local therapy only to contralateral eye

ICIR Stage at Diagnosis (N=60)